Search Results (430)

The BRAF V595E mutation analysis in canine urothelial carcinomas (UCs) has found its way into routine diagnostics, but no data analysis has been published until now. The present study aimed to estimate the distribution of age, sex, and breed in 8365 canine diagnostic samples submitted for BRAF mutation analysis during 2018–2024. The specimens included 8215 urine samples, 17 cytological, and 133 histopathological specimens, and were submitted in cases of suspected UC, to rule out UC, or for screening purposes. All samples were tested for the BRAF V595E mutation using droplet digital PCR (ddPCR). The data were statistically analysed and logistic regression models (Odds Ratio (OR)) were calculated. Compared to samples from mixed-breed dogs, the specimens from Scottish Terriers (OR: 4.21), Shetland Sheepdogs (OR: 2.65), Beagles (OR: 2.33), Fox Terriers (OR: 1.92), Staffordshire Bull Terriers (OR: 1.86), Magyar Vizslas (OR: 1.77), Chihuahuas (OR: 1.70), and West Highland White Terriers (OR: 1.43) had a significantly increased probability of the presence of BRAF mutation indicating UC. The youngest BRAF-positive dogs of these predisposed breeds (n = 4) were 5 years old. In conclusion, screening tests in predisposed breeds may be recommended from the age of 5 years. Full article

Background/Objectives: Papillary thyroid microcarcinoma (MPTC), a subset of papillary thyroid carcinoma (PTC), is increasingly detected with advanced imaging. While most MPTCs are indolent, some exhibit aggressive behavior, complicating clinical management. The BRAF V600E mutation, common in PTC, is linked to aggressive features, and its allele frequency (AF) may serve as a biomarker for tumor aggressiveness. This study explored the association between BRAF V600E AF and aggressive histopathological features in MPTC. Methods: Data from 1 January 2016 to 23 December 2023 were retrieved from two McGill University teaching hospitals. Inclusion criteria comprised patients aged ≥ 18 years with thyroid nodules ≤ 1 cm, documented BRAF V600E mutation and AF results, and available surgical pathology reports. Tumor aggressiveness was defined as the presence of lymph node metastasis, aggressive histological subtype (tall cell, hobnail, columnar, solid/trabecular or diffuse sclerosing), extra thyroidal extension, or extensive lymphovascular extension. Associations were explored using t-tests. Results: Among 1564 records, 34 met the inclusion criteria and were included in analyses. The mean BRAF V600E AF was significantly higher in aggressive tumors (23.58) compared to non-aggressive tumors (13.73) (95% CI: −18.53 to −1.16, p = 0.03). Although not statistically significant, trends were observed for higher BRAF V600E AF in tumors with lymph node metastasis (mean AF: 25.4) compared to those without (mean AF: 16.67, p = 0.08). No significant difference was noted in BRAF V600E AF by histological subtype (mean AF for aggressive: 19.57; non-aggressive: 19.15, p = 0.94). Conclusions: Elevated BRAF V600E AF is associated with aggressive behavior in MPTC, highlighting its potential as a biomarker to inform treatment strategies. Larger studies are warranted to validate these findings and enhance clinical management of MPTC patients. Full article

The clinicopathologic and molecular features of serrated lesions with dysplasia in inflammatory bowel disease (IBD) remain poorly understood. We examined a total of 2396 patients treated for IBD at the University of Szeged between 2011 and 2023. Among them, 177 (7%) patients were diagnosed with colorectal neoplasia, of which only 11 (6%) had serrated dysplasia (n = 13). Of the 13 lesions, 5 (38%) showed features of sessile serrated lesion (SSL)-like dysplasia; 1 (8%) exhibited characteristics of traditional serrated adenoma (TSA)-like dysplasia; 6 (46%) were classified as serrated dysplasia, not otherwise specified (NOS); and 1 (8%) displayed mixed features of SSL-like and TSA-like dysplasias. At the time of the serrated dysplasia diagnosis, the mean age of the patients was 56 years. Ten (91%) patients had ulcerative colitis, and one (9%) had Crohn’s disease. Pancolitis was observed in seven (64%) patients. The mean duration of IBD at the time of the serrated dysplasia diagnosis was 26 years. Most lesions (n = 9; 69%) were found in the left colon, including SSL-like dysplasia (3/5; 60%) and serrated dysplasia NOS (5/6, 83%). Eleven (85%) lesions had a polypoid endoscopic appearance. The mean size of the serrated dysplasia was 0.8 cm. Most lesions (n = 8; 62%) showed low-grade dysplasia. Serrated dysplasia was often associated with conventional (n = 3; 27%) or nonconventional dysplasia (n = 3; 27%). During the follow-up, 5 (45%) of the 11 patients developed colorectal cancer, including 3 patients with serrated dysplasia NOS, 1 with SSL-like dysplasia, and 1 with TSA-like dysplasia. Whole-exome sequencing revealed that the SSL-like dysplasia harbored mutations in BRAF (p.V600E), MLH1, KRAS, PTEN, POLE, KMT2C, and/or EXT1, whereas the serrated dysplasia NOS showed mutations in TP53, POLG, BRAF (p.G469A), KMT2C, and/or EXT1. One patient with both SSL-like dysplasia and mixed SSL-like/TSA-like dysplasia carried a pathogenic MUTYH (p.R217H) mutation, along with mutations in MADD. Serrated dysplasia was rare in IBD, with a prevalence rate of 6%. The SSL-like dysplasia exhibited distinct clinicopathologic and molecular characteristics compared with its sporadic counterpart. Similarly, serrated dysplasia NOS displayed unique molecular features compared with SSL-like dysplasia and could carry a higher risk of malignancy. Full article

The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, we combined short-term cell viability assays with long-term regrowth assays following drug removal over a period of three weeks. This allowed assessment of regrowth after therapy discontinuation. We tested the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib) on BRAF-V600E mutant CRC patient-derived organoids (PDOs). Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by rapid regrowth after drug removal, mirroring clinical outcomes. EGFR inhibition in BRAF-V600E mutant PDOs led to activation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R). The IGF1R/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented regrowth of CRC PDOs, and improved the anti-tumour response in an in vivo model. PDO regrowth assays allow the identification of pathways driving tumour recurrence. IR/IGF1R-inhibition prevents regrowth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC Full article

Lung cancer remains the leading cause of cancer-related death in the US and worldwide. Recent advances in molecular profiling and targeted therapies have revolutionized the management of non-small cell lung cancer (NSCLC), particularly in oncogene-driven subtypes. These therapies selectively target key molecular alterations in EGFR, ALK, KRAS, ROS1, MET, RET, ERBB2 (HER2), BRAF V600E, and NTRK, resulting in substantial improvements in survival rates and quality of life for lung cancer patients. However, disparities in molecular diagnostics and precision treatments persist, disproportionately affecting minority patients. These inequities include underrepresentation in clinical trials, disparities in molecular testing, and barriers to treatment access. The limited participation of racial and ethnic minorities in landmark clinical trials raises concerns about the generalizability of findings and their applicability to diverse populations. In this review, we examine the current landscape of molecular diagnosis and precision medicine in minority patients with oncogene-driven lung cancer, highlighting challenges, opportunities, and future directions for achieving equity in precision oncology. Additionally, we discuss differences in the prevalence of oncologic driver mutations across populations and emphasize the urgent need for greater diversity in clinical research. Addressing these gaps is critical to improving survival outcomes and ensuring equitable access to personalized lung cancer care for all patients. Full article

Background: Comprehensive molecular profiling is essential for precision oncology in non-small cell lung cancer (NSCLC). However, genomic data from Eastern European populations, including Romania, remain limited. Methods: We analyzed 398 consecutive NSCLC cases tested at the PATHOS Molecular Pathology Laboratory (Cluj-Napoca, Romania) between April 2024 and February 2025 using the Ion Torrent™ Genexus™ System and the Oncomine™ Dx Target Test, which evaluates SNVs/indels in 46 genes, fusions in 23 genes, and CNVs in 19 genes from FFPE samples. Results: The cohort was predominantly male (66%) with a median age of 67 years. Adenocarcinoma represented 70% of cases with known histology. Genomic profiling revealed a high frequency of actionable alterations. KRAS mutations were the most common (29.1%), with p.G12C detected in 10.3% of all the cases. EGFR mutations were present in 14.3% of patients, mostly exon 19 deletions and L858R substitutions. BRAF alterations (5.3%) included both V600E and non-V600E variants. RET alterations were detected as eight missense mutations, two canonical fusions (KIF5B–RET, CCDC6–RET), one amplification, and three transcript imbalances. EML4-ALK fusions (1.77%), ERBB2 mutations/amplifications (3.0%), and FGFR1/FGFR3 amplifications were also observed. Conclusions: This study provides the first large-scale molecular snapshot of NSCLC in Romania. While the overall genomic profiles align with Western populations, the higher frequency of KRAS p.G12C and FGFR amplifications highlights the value of region-specific data to support targeted therapies in Eastern Europe. Full article

The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was tested in pCRC cell lines and patient-derived cancer spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor ganetespib (Gan, STA-9090) and standard-of-care therapies. A total of 26.97% pCRCs showed strong tumoral Hsp90α/β expression (Hsp90α/β > 40%), which correlated with reduced PFS (HR: 3.785, 95%CI: 1.578–9.078, p = 0.003) and OS (HR: 3.502, 95%CI: 1.292–9.494, p = 0.014). Co-expression of Hsp90α/β > 40% with its clients BRAF-V600E and Her2/neu aggravated the prognosis (BRAF-V600E mutated: PFS, p = 0.002; OS, p = 0.012; Her2/neu score3: PFS, p = 0.029). The prognostic cut-off Hsp90α/β > 40% was also a predictor for response to Pim-based therapy. Pim efficacy was increased in combination with 5-FU, 5-FU + oxaliplatin, and 5-FU + irinotecan (all p < 0.001). Pim induced sensitization to all chemotherapies in HT-29 (p < 0.001), Caco-2 (p < 0.01), and HCT116 (p < 0.05) cells. Pim combined with encorafenib in HT-29 and with trastuzumab in Caco-2 cells was most effective in dual-target inhibition approaches (HT-29: p < 0.005; Caco-2: p < 0.05). The anti-cancer effect and chemosensitization of Pim-based therapy were prospectively confirmed in PDCS directly generated from Hsp90α/β > 40% pCRCs. Protein profiling combined with functional drug testing stratifies Hsp90α/β > 40% pCRC patients diagnosed with UICC IIb-IV for effective Pim-based therapy. Full article

Introduction: The combination of BRAF and MEK inhibitors (BRAF/MEKi) has significantly improved survival in melanoma patients with BRAF V600 mutations. However, these agents can cause cardiovascular (CV) toxicity, compromising efficacy. This study evaluated the CV adverse events (cAEs) associated with BRAF/MEKi using the U.S. FDA Adverse Event Reporting System (FAERS) to identify new signals of disproportionate reporting (SDRs). Methods: Descriptive and disproportionality analyses were conducted on reports listing dabrafenib (D), vemurafenib (V), encorafenib (E), trametinib (T), cobimetinib (C), or binimetinib (B) as suspects in monotherapy or combination therapy (D + T, V + C, E + B), with melanoma as the indication and at least one cAE. Standardized MedDRA Queries (SMQs) related to cAEs, including bradyarrhythmias and tachyarrhythmias, cardiac failure, cardiomyopathy, thrombotic events, ischaemic heart disease, and myocarditis/pericarditis, were analyzed. Results: Of the 14,077,067 reports retrieved, 18,370 (0.1%) were linked to BRAF/MEKi, with 1591 (8.7%) reporting cAEs, primarily in combination therapy (n = 1268). Disproportionality analysis identified 64 clinically relevant SDRs, most of which were unexpected. Notable findings included bradyarrhythmias, such as QT prolongation with D + T (n = 59; Reporting Odds Ratio, ROR = 5.09, 95% Confidence Interval, CI = 3.94–6.58), cardiac failure with V + C (29; 3.76, 2.6–5.42), and tachyarrhythmias, particularly atrial fibrillation with D + T (99; 2.37, 1.94–2.89). Among embolic and thrombotic events, clinically significant SDRs were observed for disseminated intravascular coagulation with D + T (38; 10.22, 7.42–14.06) and pulmonary embolism with V + C (22; 2.79, 1.83–4.24). Conclusions: Our findings underscore the need for comprehensive CV monitoring in patients receiving BRAF/MEKi therapy to prevent or detect cAEs early and reduce treatment-related risks, particularly in high-risk populations. Full article

Background and Objectives: Lynch syndrome (LS), an autosomal dominant condition arising from germline mutations in mismatch repair (MMR) genes, is a major cause of hereditary early-onset colorectal cancer (CRC). Although patients diagnosed before age 50 represent a critical subgroup where Lynch syndrome might be more prevalent, data on the precise frequency, clinical outcomes, and molecular correlates remain heterogeneous across studies. This systematic review was conducted to (1) estimate the prevalence of MMR deficiency (dMMR) and confirmed LS in patients diagnosed with CRC before the age of 50, and (2) examine immunohistochemistry (IHC) mismatch repair testing patterns and associated molecular findings (BRAF mutations, MLH1 promoter hypermethylation, somatic MMR gene alterations). Methods: Following a predefined search strategy in PubMed, Scopus, and Web of Science, five relevant studies were identified (n = 5). Each study comprised patients younger than 50 who underwent IHC-based tumor screening. Data extraction covered demographic details, number of patients tested, proportion with abnormal IHC, frequency of somatic or germline MMR gene mutations, and method of classification into sporadic dMMR vs. LS. Quality assessment was performed using recommended scales for observational studies. Results: Among 5 studies totaling 960 early-onset CRC patients, the frequency of dMMR CRC ranged from 8.4% to 19.1%. The confirmed prevalence of LS among all young-onset CRC was between 5.0% and 5.9% in three studies but reached 8.9% in another and 5.1% in yet another. Across all studies, the presence of right-sided tumors and histopathological features such as tumor-infiltrating lymphocytes were more common in dMMR cancers. Incorporation of MLH1-promoter hypermethylation and/or BRAF V600E mutation testing aided discrimination of sporadic dMMR CRC from germline LS cases. Conclusions: The prevalence of LS in CRC patients younger than 50 is clinically significant, at approximately 5–9%. Routine IHC-based MMR screening is both feasible and effective for detecting LS in early-onset CRC. Further research is needed to standardize universal testing protocols, delineate the role of additional molecular assays, and ensure comprehensive genetic counseling for at-risk individuals. Full article

Background/Objectives: Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP). Methods: Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses. Results: The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells. Conclusions: These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study. Full article

Anaplastic thyroid carcinoma (ATC) is the rarest and most aggressive form of thyroid cancer, marked by a poor prognosis and resistance to conventional treatments. Like many malignancies, ATC has a complex genetic landscape, with numerous mutations driving tumor initiation, progression, and therapeutic resistance. However, recent advances in molecular research have expanded our understanding of these genetic alterations, paving the way for new targeted treatment strategies. Currently, therapies targeting specific genetic mutations, such as BRAF and MEK, show promise, but their effectiveness is limited to patients harboring these mutations. To explore broader therapeutic possibilities, we conducted a comprehensive literature review using the PubMed database and Google to identify studies on key genetic mutations in ATC. By leveraging these molecular insights, we aim to highlight potential therapeutic avenues that could enhance treatment options and improve patient outcomes. Full article

Background: Splenic B-cell lymphomas and leukaemias include hairy cell leukaemia, splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma, and splenic B-cell lymphoma/leukaemia with prominent nucleoli. The main diagnostic challenge is to differentiate between splenic B-cell lymphomas and leukaemias due to highly overlapping clinical, morphologic, and phenotypic features in the absence of splenectomies for diagnostic purposes. Case presentation: We describe a case of a 78-year-old woman who presented with weight loss and was subsequently found to have pancytopenia, lymphocytosis, and splenomegaly. Peripheral blood smear showed a homogenous population of small- to medium-sized lymphocytes having oval nuclei, condensed chromatin, and villous cytoplasmic projections. Bone marrow showed B-cell infiltrate in a predominantly intrasinusoidal pattern. Except for cyclin D1 and BRAF, the immunophenotype was similar to that of hairy cell leukaemia. This was further supported by the lack of BRAF p.V600E mutation by polymerase chain reaction. A diagnosis of splenic diffuse red pulp small B-cell lymphoma was thus favored based on the lack of cyclin D1 expression and pattern of infiltration in the bone marrow biopsy. Conclusions: Awareness of this infrequent clinical presentation and immunophenotype of splenic diffuse red pulp small B-cell lymphoma is crucial for diagnosis and devising appropriate therapeutic strategies for the patient. Full article

BRAF mutations are critical drivers in cancers such as melanoma, colorectal cancer, and non-small-cell lung cancer. The most common mutation, BRAF V600E, is a key therapeutic target. Targeted treatments with BRAF and MEK inhibitors have significantly improved progression-free and overall survival in melanoma patients. However, in cancers like metastatic colorectal cancer, BRAF mutations are associated with poor outcomes due to aggressive disease behavior and resistance to conventional chemotherapy. Despite progress, resistance to BRAF/MEK inhibitors remains a major challenge, often driven by secondary mutations in the mitogen-activated protein kinase (MAPK) pathway, activation of alternative pathways such as phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), or changes in the tumor microenvironment. These challenges have motivated ongoing research into combining BRAF inhibitors with immunotherapies to enhance and prolong treatment effectiveness. Future research must also account for the role of the cancer’s tissue of origin, as the biological context significantly influences response to targeted therapies, highlighting the need for a deeper understanding of tumor biology, micro-environment, and genetics. Full article

Background/Objectives: The BRAF-mutation is a poor prognostic factor in colorectal cancer (CRC). There is a need for real-world data in low-middle-income countries regarding clinical characteristics, outcomes, and treatment strategies. This study aims to describe progression-free survival (PFS) and in the first- and second-line setting and sequences of treatment regimens. Methods: We retrospectively analyze patients from ten oncology centers in Argentina, diagnosed with BRAF^V600E-mutated advanced CRC between January 2014 and July 2023. Results: A total of 161 patients with metastatic CRC and BRAF^V600E-mutation. The median age was 58.5 (IQR 47–69), and 21.7% were MMR-deficient (dMMR). Of these patients, 93.8% received first-line treatment. With a median follow-up of 23 months (95% CI 16.5–33.4 months), the median PFS was 9 months (95% CI 7.4–10.5 months). The most common regimen in first line setting was doublet chemotherapy plus anti-VEGF for 49% of the patients. Twenty-six percent of the patients received BRAF inhibitors in the second-line setting, with a median PFS of 5.2 months (95% CI 4.9—NR); the overall response rate (ORR) was 10.5%. Conclusions: This study represents, to the best of our knowledge, the largest published real-world cohort of BRAF^V600E-mutated CRC in Latin America. The heterogeneity of the treatments reflects the existence of barriers to access to high-cost drugs in our country. Cooperative efforts are needed to understand the particular characteristics of this subgroup of patients. Full article

B-RAF is a serine/threonine kinase that plays a crucial role in the MAPK signaling pathway, regulating cell proliferation and survival. Mutations in B-RAF, particularly V600E, are associated with several malignancies, including melanoma, colorectal cancer, and non-small cell lung cancer, making it a key therapeutic target. The development of B-RAF inhibitors, such as Vemurafenib, Dabrafenib, and second-generation inhibitors like Encorafenib, has led to significant advancements in targeted cancer therapy. However, acquired resistance, driven by MAPK pathway reactivation, RAF dimerization, and alternative signaling pathways, remains a major challenge. This review explores the molecular mechanisms of B-RAF inhibitors, their therapeutic efficacy, and resistance mechanisms, emphasizing the importance of combination strategies to enhance treatment outcomes. The current standard of care involves B-RAF and MEK inhibitors, with additional therapies such as EGFR inhibitors and immune checkpoint blockades showing potential in overcoming resistance. Emerging pan-RAF and brain-penetrant inhibitors offer new opportunities for treating refractory cancers, while precision medicine approaches, including genomic profiling and liquid biopsies, are shaping the future of B-RAF-targeted therapy. Full article